Polygenic risk and lifestyle factors independently influence dementia risk

1. In this retrospective cohort study, patients with high polygenic risk scores and unhealthy lifestyle factors were more likely to be diagnosed with dementia than patients with low polygenic risk scores or healthy lifestyle factors.

2. Polygenic risk scores and lifestyle factors independently influenced dementia risk.

Evidence Rating Level: 2 (Good)

Study Rundown: The etiology of dementia is complex and is influenced by both genetic risk and environment. Still, it is unclear whether there is an interaction between genetic risk and lifestyle factors or if both of these processes influence dementia risk independently from the other. In this large retrospective cohort, patients with high polygenic risk scores and unhealthy lifestyle factors were more likely to be diagnosed with dementia than patients with low polygenic risk scores or healthy lifestyle factors. These two factors did not interact, however, as polygenic risk scores and lifestyle factors separately influenced dementia risk.

Given the large cohort, it is very likely that for this study population dementia risk is independently influenced by polygenic risk scores and lifestyle. However, it is important to note that this study excluded those without European Ancestry, so it is unclear if these results generalize to other populations, especially those with higher genetic risk for hypertension and cardiovascular disease. In addition, the mean age of participants was relatively young, and it is unclear if gene by lifestyle interactions would be more apparent for an older patient population.

Click to read the study in JAMA

Relevant Reading: Validation of a polygenic risk score for dementia in black and white individuals

In-Depth [retrospective cohort]: 196,383 participants from the UK Biobank Study were retrospectively followed for a median of 8 years at 22 assessment centers in the UK. Analyses were restricted to those who were 60 or older at baseline, did not have cognitive impairment or dementia at baseline, and were of European ancestry. Polygenic risk scores were compiled from 249,273 SNPs related to Alzheimer’s Disease and dementia, while lifestyle risk scores were compiled from a composite score of 4 well-defined dementia risk factors (smoking, physical activity, diet, and alcohol). All-cause dementia was the primary endpoint and was assessed from the Hospital Episode Statistics for England, Scottish Morbidity Record data for Scotland, the Patient Episode Database for Wales, the National Health Service Digital for England and Wales, and the Information and Statistics Division for Scotland. All models were adjusted for age, sex, education, socioeconomic status, 3^rd degree relatedness of individuals in the sample, and the first 20 principal components of ancestry. Polygenic risk was normally distributed and not associated with lifestyle factors, except for a very low association with physical activity (Odds Ratio 1.01; CI₉₅ 1.00 to 1.02). Dementia risk increased with polygenic risk scores, with the hazard ratio (HR) between the lowest and highest groups of risk scores being 1.91 (CI₉₅ 1.64 to 2.23). Dementia risk increased with lifestyle risk scores, with the HR between the lowest and highest groups of risk scores of 1.35 (CI₉₅ 1.15 to 1.58). Additional adjustment for the other risk score did not change the associations for either polygenic or lifestyle risk scores. There was no interaction between polygenic risk score and lifestyle factors (p = 0.99).

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